Thyroid hormone mediates a remarkable range of actions in many tissues and organs. These actions promote tissue development as well as tissue function in adults. The breadth of different responses, including in the nervous, sensory and endocrine systems among other systems, raises a key question concerning the mechanisms that determine the nature, time and place of a response to thyroid hormone. How does this hormone elicit so many different cellular responses? Thyroid hormone receptors (TR) act as ligand-regulated transcription factors and occupy a key position in the chain of events that elicit the cellular response. Two receptor genes, Thrb and Thra, encode several TR isoforms that are expressed in different developmental and tissue-specific patterns. Thus, the ability to express a given receptor isoform in a particular tissue confers a specific response. This project investigates the mechanisms that determine the tissue-specific functions of TRb1 and TRb2 receptor isoforms encoded by the Thrb gene. The aim is to reveal the developmental and homeostatic functions for these TR isoforms and to investigate other factors that modify the activity of the receptors in different tissues. We use genetic model systems to address: 1. Functions of TRb1 and TRb2 isoforms in differentiation and homeostasis. To determine the biological functions of TRb isoforms, we study mouse models in which TRb1 or TRb2 have been deleted. These studies have identified novel, cell-specific expression patterns of TRb1 in the cochlea and endocrine tissues including the anterior pituitary and adrenal cortex. In the auditory system, we determined that TRb1 maintains hearing during adulthood and aging. The findings suggest that thyroid hormone may be a factor that counters age-related hearing loss, which is widespread in human populations. In the adrenal gland, TRb1 is expressed in a previously unrecognized sexually-dimorphic cortical cell population and mediates hypertrophic responses, suggesting direct actions for thyroid hormone in adrenal gland functions. 2. Factors that influence TR activity in tissue-specific fashion. We investigate factors including deiodinase enzymes that activate and inactivate thyroid hormone ligand, as well as plasma membrane transporters that mediate the cellular uptake of thyroid hormone from the circulation into specific cells. We found that in several target tissues, (cochlea, retina) deiodinases provide critical control over TR activity. Recent evidence indicates that tissues such as the retina and the testis are subject to control by type 3 deiodinase that degrades hormone to limit the availability of ligand. The findings support the proposal that specific receptor isoforms and deiodinases function in close cooperation in a given tissue to determine the nature and timing of the response. We have also found that membrane transporters that control the cellular uptake of thyroid hormone are critical for cochlear development and potentially for the development of other tissues. 3. Target genes for TRb isoforms in natural tissues. To study this critical question regarding the mechanisms by which thyroid hormone stimulates cellular differentiation and function, we investigate the mechanisms of transcriptional regulation of candidate target genes for TRb isoforms. These studies involve a variety of molecular and genomic approaches, to identify changes in gene expression patterns and genomic DNA binding sites for these receptor isoforms in different tissues.